EA014239B1 - Diaza-spiro-[4.4]-nonane derivatives as neurokinin (nk1) antagonists - Google Patents

Abstract

This invention relates to substituted diaza-spiro-[4.4]-nonane derivatives of general formula (I) and the pharmaceutically acceptable acid or base addition salts thereof, the stereochemical isomeric forms thereof, the N-oxide form thereof, wherein all substituents are defined as in Claim 1. having neurokinin antagonistic activity, in particular NK1 antagonist ic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment and/or prophylaxis of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (COPD) and micturition disorders such as urinary incontinence.

Description

Field of Invention

This invention relates to substituted derivatives of diaz-spiro [4,4] nonane having antagonistic activity against neurokinin, in particular antagonistic activity towards ΝΚμ to methods for producing these derivatives, to compositions containing these derivatives, and to their use as medicines, in particular for the treatment and / or prevention of schizophrenia, vomiting, anxiety and depression, irritable bowel syndrome (ΙΒ8), circadian rhythm disturbances, preeclampsia, nociception, pain, in particular and visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (ΟΟΡΌ) and micturition disorders such as urinary incontinence.

State of the art

Tachykinins belong to the family of short peptides that are widely distributed in the central and peripheral nervous system of mammals (Waitapb aib Operre, Tteibk Ryattaso1. 8: 17: 255-259 (1996); Lipbybd, Sap. 1. Ryukyu1. Ryattaso1. 73: 908- 914 (1995); Madd1, Oei. Ryattaso. 1 26: 911-944 (1995); Veda e! A1., Ryattaso 1. Veu. 46 (1994). They have a common C-terminal sequence of P11e-Haa-C1u-Rei-Me1-H ₂ . It is believed that tachykinins released from peripheral sensory nerve endings are involved in neurogenic inflammation. In the spinal cord / central nervous system, tachykinins can be involved in the transmission / perception of pain, as well as in some autonomic and behavioral reflexes. The three main tachykinins are substance P (8P), neurokinin A (ΝΚΑ) and neurokinin B (ΝΚΒ), which have selective affinity for three different subtypes of neurokinin receptors, denoted by ΝΚι, ΝΚ ₂ and ΝΚ ₃ , respectively. However, the results of functional studies on cloned receptors suggest that there are strong functional cross-interactions between the three tachykinins and the corresponding neurokinin receptors (Madd1 apb 8c11 \\ 'ag1x. Ttepbk Ryattaso.1. 8g 18: 351-355 (1997)).

Species differences in the structure of receptors ΝΚ ₁ cause different activity of antagonists ΝΚ ₁ in different species (Madd1, Oep. Ryattaso. 1: 26: 911-944 (1995); Veda e! A1., Ryattaso.. Veu. 46 (4): 551-599 (1994)). The human receptor ΝΚ _{1 is} very similar to the receptor ΝΚ _{1 of} guinea pigs and gerbils, but is very different from the rodent receptor гι. To date, the development of neurokinin antagonists has resulted in a number of peptide compounds that are too actively metabolized to be used as pharmaceutically active substances (Loptote 1. e! A1., E '& P 8 (1): 5-23 (1995)).

Tachykinins mediate schizophrenia, depression (related to stress), anxiety, vomiting, inflammatory responses, smooth muscle contraction, and pain. Based on neurokinin antagonists, drugs are being developed against vomiting, anxiety and depression, irritable bowel syndrome (ΙΒ8), circadian rhythm disturbances, visceral pain, neurogenic inflammation, asthma, urination disorders and nociception. In particular, antagonists ΝΚ ₁ have a high therapeutic potential for vomiting and depression, and antagonists ΝΚ ₂ have a high therapeutic potential for asthma. Antagonists ΝΚ ₃ can be involved in the treatment of pain / inflammation (O1 atbta, O. e! A1. Exp. Orsh. Thyet. Ra1epK 10 (6): 939-960 (2000)) and schizophrenia.

Schizophrenia

Recently, an antagonist of ΝΚ ₃ 8B142801 (8th) has been shown to have antipsychotic effects on patients with schizophrenia without affecting negative symptoms (Aguayo, L. AC'P Meeypd, Eseteb 2001). Activation of ΝΚι receptors causes anxiety, stressful events lead to an increase in plasma P (8P) levels, and ΝΚι antagonists, according to published data, have an anxiolytic effect on some animal models.

The antagonist ΝΚι MV-869, obtained from Megsk, has an antidepressant effect in case of deep depression, however, these results are not reliable due to the high frequency of response to placebo. In addition, it was shown that the antagonist ΝΚ ₁ (8) -OB205171 from S1a.xo- \ Ve1sote increases the release of dopamine in the frontal lobe of the cerebral cortex, but not in the striatum (E_e) eipe e! a1. 8os. 'eigro8c1.,' ouber 2001). Therefore, it can be assumed that antagonists of ΝΚ ₃ in combination with antagonists of ΝΚ1 have a beneficial effect on both positive and negative symptoms of schizophrenia.

Anxiety and Depression

Depression is one of the most common affective disorders in modern society with a high and increasing frequency of diseases, especially among young members of the population. Currently, the incidence of deep depression (MOO, E8M-1U) is 1025% among women and 5-12% among men, while in about 25% of patients, the lifetime of MEE is recurrent, with no complete recovery between seizures and overlapping dysthymic disorder. There is a high degree of joint incidence of depression and other mental disorders, in particular in the young population, depression is often associated with drug and alcohol dependence. Since depression mainly affects people between the ages of 18 and 44, that is, the most able-bodied part of the population, it is obvious that it is severe

- 1 014239 a burden for individuals, their families and society as a whole.

Among all therapeutic methods, antidepressant treatment is undeniably the most effective. Over the past 40 years, a large number of antidepressants have been developed and marketed. However, none of the existing antidepressants fully meets all the criteria for an ideal drug (high therapeutic and prophylactic efficacy, speed, complete short-term and long-term safety, simple and convenient pharmacokinetic parameters), including the absence of side effects that are one or another The method limits the use of antidepressants in all groups and subgroups of patients suffering from depression.

Since there are currently no methods for treating the causes of depression, and their appearance is not expected in the near future, and there are no antidepressants effective for more than 60-70% of patients, there is a need to develop new antidepressants that would overcome the disadvantages inherent in affordable medicines.

Some evidence suggests 8P involvement in stress-related anxiety states. The introduction of 8P into the central nervous system causes a cardiovascular response that resembles the classic fight or flight response, physiologically characterized by vasodilatation of skeletal muscle and a decrease in mesenteric and renal blood flow. The indicated cardiovascular reaction is accompanied by a behavioral response observed in rodents after exposure to a harmful stimulus or stress (S1tap apb Ipdeg, Sap. I. P11ukyu1. Ryagtaso1. 73: 885-891 (1995)). Agonists and antagonists ΝΚ ₁ after systemic administration have an anxiogenic and anxiolytic effect on mice, respectively (Te1khe1ga e! A1., Eig. 1. Ryagtaso1. 311: 7-14 (1996)). The ability of antagonists ΝΚ _{1 to} inhibit 8P-induced heartbeat (or by electric shock: Ba11agb e! A1., Tgepbk P11agtaeo1. Δει. 17: 255-259 (2001)) is consistent with the indicated antidepressant / anxiolytic activity, since heartbeat plays a role in prevention danger or alarm for animals of the same species.

Receptor ΝΚ ₁ can be found throughout the limbic system and in the areas of the brain responsible for the formation of feelings of fear, which include the cerebellar tonsil, hippocampus, septum, hypothalamus, and the parietal region of the gray matter. In addition, substance P is released in the central nervous system in response to traumatic or toxic stimuli, and substance P mediated neural signaling may contribute to or contribute to the development of feelings of anxiety, fear and emotional disturbances that accompany affective disorders such as depression and anxiety . This point of view is confirmed by changes in the content of substance P in individual parts of the brain that occur in response to stressful stimuli (Vgobsh e! A1., No. igorerybek 26: 253-260 (1994)).

The introduction of substance P mimetics (agonists) into the central nervous system induces a number of protective behavioral and cardiovascular changes, including conditional antipathy to the site (Yeshoy, Exp. Vgash. Century 73: 354-356 (1988)), enhanced sound start -reflex (Kgake e! a1, BeNau. You. Century. 63: 81-88 (1994)), distress vocalization, avoidance reaction (Kgateg e! a1., 8slieie 281: 1640-1645 (1998)) and anxiety on elevated cruciform labyrinth (Adshag apb Vgapbao, Ryukyu. 1 BeNau. 60: 1183-1186 (1996)). These compounds do not affect motor activity and coordination of movements on a rotating apparatus or on the ability to move in a cell adapted for active movements. The downregulation of the biosynthesis of substance P is observed in response to the introduction of known anxiolytic and antidepressant drugs (Vbshche e! A1., No. igorerybek 26: 253-260 (1994); 8 Lygauata e! A1., Vgash. Vek. 739: 70-78 (1996 )). Similarly, the vocal response induced in guinea pigs by the administration of an ΝΚ1 agonist into the central nervous system can be suppressed by the action of antidepressants such as imipramide and fluoxetine, as well as L-733060, an antagonist of ΝΚ ₁ . The results obtained in the conducted studies suggest that blockade of receptors ΝΚ1 in the central nervous system leads to suppression of psychological stress by a mechanism reminiscent of the mechanism of action of antidepressants and anxiolytics (Virschak apb Kgateg, Tgepbk Ryagshaso1. 8c1. 20: 1-12 (1999) ), but it does not have the side effects characteristic of currently existing drugs.

Vomiting

Nausea and eruption of vomit are the most unpleasant side effects of anti-cancer chemotherapy. They reduce the quality of life and may encourage patients to postpone the use of drugs that can help them, or completely abandon their use (Kpk e! A1., 1. Cl. Opso1, 3: 1379-1384 (1985)). The frequency of occurrence, the intensity and nature of the vomiting is determined by various factors, such as the type, dose and route of administration of the chemotherapeutic agent. As a rule, early or acute vomiting begins within the first 4 hours after administration of a chemotherapeutic agent, reaches a peak in the range from 4 to 10 hours and decreases between 12 and 24 hours. Delayed vomiting (developing after 24 hours and lasting for 3-5 days after chemotherapy) is observed after the introduction of most chemotherapeutic agents with intense vomiting effect (level 4 and 5 in accordance with Nekke! N e! a1., 1. Cl. Opso1. 15: 103 (1997)). Intensive anti-cancer agents

- 2 014239 emetic effect, including cisplatin, cause acute vomiting in more than 98% and delayed vomiting in 60-90% of people suffering from cancer.

Animal chemotherapy models, such as cisplatin-induced vomiting in ferrets (Kibb aib Laufot, No. giattattoodu 33: 1607-1608 (1994); Laufot apb Kibb, Sapseg. 8it. 21: 117-135 (1996)), make it possible to successfully predict clinical efficacy 5-HT ₃ receptor antagonists. Although this model helps to find a way to successfully treat cancer patient nausea caused by chemotherapy and radiation, 5-HT ₃ antagonists, such as ondansetron and granisetron (alone or in combination with dexamethasone), effectively suppress the phase of acute vomiting (within the first 24 hours) but they only reduce delayed vomiting (> 24 hours), moreover, with low efficiency (Ee Mi1beg e! a1., Appia1k o! 1n! egpa1 Mebushu 113: 834-840 (1990); Koya, Opso1odu 50: 163-167 ( 1993)). Despite the fact that currently there are effective ways to prevent acute and delayed vomiting, 50% of patients still suffer from delayed vomiting and / or nausea (Lpbetebs 8 and Lottie, Appa 1k Opso1. 9: 811-819 (1998)).

It was shown that, unlike 5-HT ₃ antagonists, antagonists are ΝΚ ₁ , such as CP-99994 (P1eb1top! E e! A1., B. Pbactaco. Exp. Thy. 266: 270-273 (1993)) and aprepitant ( also known as MK-869 or L754030; Kgateg e! a1., 8c1epse 281: 1640-1645 (1998); Ktsrshak apb Kgateg, Tgepbk Pbagtaso.1. 8sk 20: 1-12 (1999)), inhibit not only acute, but also delayed phase of cisplatin-induced vomiting in animals (Kibb e! a1., Bg. 1. Pagtaso1. 119: 931-936 (1996); Ta !! ekka11 e! a1., no. giattaslodu 39: 652-663 (2000)) . It has also been shown that antagonists ΝΚ ₁ reduce delayed vomiting in men in the absence of concomitant therapy (Sosdiu! E! A1., Eig. 1. Sapseg 37: 835-842 (2001); Lauap e! A1., N. Epd1. B. Mob. 340: 190-195 (1999)). Moreover, it has been shown that co-administration of ΝΚ ₁ antagonists (such as MK-869 and C1-11974, also known as ezlopitant) with dexamethasone and 5-HT ₃ antagonists additionally helps prevent acute vomiting (Satrok e! A1., 1. C1sh Opso1. 19: 1759-1767 (2001); Nekke! B e! A1., Cl. Opso1. 17: 338-343 (1999)).

Neurokinin ΝΚ ₁ receptors _{of the} central nervous system play a key role in the regulation of vomiting. Antagonists ΝΚ ₁ actively prevent vomiting caused by a wide range of stimuli (Wa! Kop e! A1., Vg. 1. Pagtaso1. 115: 84-94 (1995); Ta !! ekk11 e! A1., #Igorbattaso.1. 35: 1121 -1129 (1996); Medepc e! A1., 1. Pattaso 1. Exp. Th. 302: 696-709 (2002)). It is believed that these compounds act by blocking receptors ΝΚ ₁ in the core of the central nervous system. Therefore, for the manifestation of the antiemetic activity of these compounds, in addition to the antagonistic action with respect to ΝΚ ₁ , a necessary condition is their penetration into the central nervous system. Ferret-induced loperamide-induced vomiting can be used as a quick and reliable model for screening antiemetic activity of antagonists ΝΚ ₁ . In addition, the possibility of using these compounds for the treatment of both acute and delayed phases of vomiting induced by cisplatin was demonstrated on the corresponding model of ferrets (Kibb e! A1., Bg. 1. Pagtaso1. 119: 931-936 (1994)). This model allows the study of both acute and delayed vomiting after cisplatin administration and has confirmed sensitivity to 5-HT ₃ receptor antagonists, glucocorticoids (8at e! A1., Eig. 1. Pagtaco1. 417: 231-237 (2001)) and other pharmacological agents. If a new antiemetic is not able to treat both acute and delayed phases of vomiting, it is unlikely to find application in the clinic.

Visceral pain and irritable bowel syndrome (ΙΒ8)

Visceral sensation refers to all sensory information that comes from the internal organs (heart, lungs, GI tract, hepatobiliary tract and urogenital tract) to the central nervous system, where sensation awareness occurs. The primary ways in which sensory information is transmitted from internal organs to the brain stem and viscerosomatic sections of the cerebral cortex include the vagus nerve with nodous ganglia and primary sympathetic afferent nerves with posterior root ganglia (EX) and second-order neurons from the spinal horn. Visceral pain can be caused by tumor processes (e.g., pancreatic cancer), inflammation (e.g., cholecystitis, peritonitis), ischemia, and mechanical blockage (e.g., stones in the ureter).

The medical treatment of visceral pain associated with organic disorders (in this case, cancer of the internal organs) is still based on the use of opiates. Recent results suggest that inorganic visceral disorders, such as irritable bowel syndrome (1B8), extracardiac chest pain (J’C’P) and chronic pelvic pain, may result from a state of visceral hyperalgesia. This condition is characterized by the fact that physiological, non-painful visceral stimuli (for example, bloating) lead to an awareness of the sensation of pain due to a decrease in the pain threshold. Visceral hyperalgesia may reflect a state of prolonged post-inflammatory restoration of the threshold for depolarization of the membrane of neural synapses in the visceral sensory pathways. Initially, inflammation can occur at the periphery (for example, infectious gastroenteritis) or at the site of integration of visceral sensory information (inflammation of the nervous tissue in the spinal horn). Both 8P and the peptide encoded by the calcitonin gene (SSCR) have been shown to act as pro-inflammatory neuropeptides

- 3 014239 dy in the area of inflammation of the nervous tissue.

Visceral hyperalgesia, which occurs in 15-25% of the Western population, is currently considered one of the main targets of drugs developed for the treatment of functional intestinal diseases. It poses a serious socio-economic problem in terms of the cost of medical care, the cost of prescription drugs and skipping work. Currently available treatments include, but are not limited to, the use of antispasmodics (ΙΒ8 and LYSSR), agents that improve motor function (e.g., tegasorod at constipation-ΙΒδ), laxatives (constipation-ΙΒδ), and loperamide (diarrhea-ΙΒδ ) It is shown that none of these methods is very effective, especially in the treatment of pain. For the treatment of visceral algesia in patients with painful ΙΒ8, tricyclic antidepressants are used in low doses and 88ΒΙ, however, compounds of both of these classes can have a significant effect on the passage of the colon. Studies in this area have identified a significant number of molecular targets for the development of drugs against hyperalgesia. These targets include ΝΚ receptors, COEP receptor, 5-HT ₃ receptors, glutamate receptors, and the kappa opioid receptor. Ideally, a visceral analgesic should block the increase in sensory transmission from the internal organs to the central nervous system, without affecting the normal physiological homeostasis of the LC tract, including the provision of propulsive food advancement, absorption, secretion and sensitivity.

There is an obvious association between tachykinin and the visceral nociceptive signaling pathway. A number of preclinical publications on the role of receptors ΝΚ ₁ , ΝΚ ₂ and ΝΚ ₃ in the formation of sensations of visceral pain and visceral hyperalgesia indicate that the receptors ΝΚ ₁ , ΝΚ ₂ and ΝΚ ₃ differently participate in different models of inflammatory hypersensitivity in rodents. Recently Katr s1 a1., 1. Ryattaso1. Exp Tieg. 299: 105-113 (2001) suggested that a general neurokinin receptor antagonist may be more active than a selective neurokinin receptor antagonist. In clinical pain conditions, including visceral pain, elevated levels of substance P and receptors ΝΚ _Β ΝΚ ₂ and ΝΚ ₃ (Lee e! A1., Sak1gosp1sgo1. 118: A846 (2000)). Given that recent tests of receptor antagonists ΝΚ ₁ as an analgesic have failed (Oo1bk! Et e! A1., C1t. Ryatt. Tyss. 67: 419-426 (2000)), to obtain a significant clinical effect, require the use of combinations of antagonists. Antagonists of receptor ΝΚ ₃ can be used as anti-hyperalgesia agents (1ιι1ί; · ι е! А1., Оак1тёп! Его1. 116: 11241131 (1999)); 1. Ryagtaso 1. Exp Tieg. 299: 105-113 (2001)). Recently, it has been shown that the participation of receptors ΝΚ1 and ΝΚ3, but not receptors ΝΚ2, at the level of the spinal cord in visceral hypersensitivity is mediated by nociceptive and non-nociceptive afferent stimuli (Oaibgeai & P1oibte, No. igoks. 1. Ley. 351: 59-62 (2003) Consequently, the combined antagonistic activity of ΝΚ _{1-2-3 is an} interesting therapeutic target for new methods of treating visceral hyperalgesia.

There are several preclinical publications on the role of receptors ΝΚ ₁ in the formation of sensation of visceral pain. Using mice with knockout of the ΝΚ ₁ receptor gene and animal models receiving ΝΚι antagonists, different researchers have shown that the ΝΚ ₁ receptor plays an important role in the development of hyperalgesia and visceral pain. The distribution of receptors ΝΚ1 and substance P indicates that they are more likely to participate in the formation of visceral pain than somatic. Indeed, substance P is found in more than 80% of visceral primary afferent nerves and only in 25% of cutaneous afferent nerves. The ΝΚι receptors are also involved in providing the motor functions of the gastrointestinal tract (Toshsh e! A1., Sak1goep1ego.1. 120: 938-945 (2001); Okapo e! A1., 1. Ryagtaso1. Exp. Tyeg. 298: 559-564 ( 2001)). Since ΝΚι antagonists have an effect on the motor functions of the gastrointestinal tract and nociception, it is believed that they can improve the symptoms of ΙΒ8.

Urinary incontinence

Urinary incontinence is caused by hyperreflexia of the bladder or detrusor (sensitive bladder). Such hyperreflection is associated with increased excitability of sensory afferent C-fibers that transmit a signal from the bladder to the spinal cord. Various factors can be the cause of the increased excitability of C-fibers, for example, it can occur after a bladder infection and chronic expansion of the bladder wall (for example, with benign prostatic hypertrophy, BPH). Therefore, treatment should be aimed at reducing the increased excitability of nerve cells. Intravesical instillation of vanilloids (for example, capsaicin) leads to a long-term improvement in detrusor hyperreflection, which is not amenable to traditional treatment with anticholinergics. As in animals, in humans, the action of vanilloids is mediated by a neurotoxic effect on the endings of sensory nerves. In the human bladder, subendothelial sensory nerves contain tachykinins, which control the increased excitability of the detrusor. This process involves peripheral receptors ΝΚ ₂ and, to a lesser extent, receptors ΝΚ ₁ . It was found that the latter are involved in increased excitability of the bladder at the level of the spinal cord. Therefore, for the treatment of increased excitability of the detrusor,

- 4 014239 to use an antagonist acting in the central nervous system ΝΚι / acting in the peripheral nervous system ΝΚ ₂ . Interestingly, activation of receptors ΝΚ ₂ increases aromatase activity in Sertoli cells. ΝΚ ₂ receptor antagonists decrease serum testosterone levels in mice, suggesting the possibility of their use for the treatment of BPH.

BACKGROUND OF THE INVENTION

AO 97/24324 (July 10, 1997), AO 97/24350 (July 10, 1997), and AO97 / 24356 (July 10, 1997) 1ap§8ep Ryattaseis Dz.ν. describe the use of compounds containing a piperidinyl moiety substituted with piperidinyl or pyrrolidinyl fragment, as antagonists of substance P (neurokinin). AO 01/94346 (December 13, 2001), R. Neuschapp-ba Vosye AS, describes the use of compounds containing a substituted diaza-spiro [4.5] decanyl fragment as antagonists of the neurokinin receptor.

The compounds of the present invention are structurally different from the compounds of the prior art in that they all contain a piperidinyl moiety substituted with a diazo spiro [4.4] nonyl moiety, and also that they have increased antagonistic activity against neurokinins when administered orally and centrally and have therapeutic potential, especially in the treatment and / or prevention of schizophrenia, vomiting, anxiety and depression, irritable bowel syndrome (ΙΒ8), circadian rhythm disturbances, preeclampsia, nocice Leptions, pains, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (SORI), and urinary disorders such as urinary incontinence.

Description of the invention

The present invention relates to new derivatives of substituted diaz-spiro [5.5] undecane corresponding to the general formula (I)

K ¹ a / V (cn ₂ ) _t / ^CH A (cn ^ / (t) _{

XN ') —Ζ — Ν Υ Ν-ΑΙΚ-Υ-A1k-b to ² XCH ₂ ) _p SHDSnH to their pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms and Ν-oxides, where

B ² is Ag ² ;

X is a covalent bond;

O is O;

B ^{1 is} selected from the group consisting of Ar ¹ -alkyl and di (Ag ¹ ) alkyl;

n and m are both equal to 1;

Ζ stands for covalent bond;

At k, p, s. | denote integers independently of one another equal to zero, 1, 2 or 3;

provided that the sums (ί + k) and (p + c |) are 3;

T is = O in the alpha position with respect to the atom Ν, and 1 is an integer equal to 0 or 1;

each A1k independently represents a covalent bond; a bivalent saturated hydrocarbon radical containing 1 carbon atom;

Υ represents a covalent bond or a bivalent radical of the formula —C (═O) -;

B is selected from the group consisting of hydrogen, alkyl, Ar ³ or He! ² ;

Ar ¹ is phenyl;

Ar ² is phenyl optionally substituted with 1 or 2 haloalkyl substituents;

Ar ³ is phenyl;

Not! ² represents a monocyclic heterocyclic radical selected from the group consisting of tetrahydrofuranyl, furanyl, thiadiazolyl, pyrazinyl and thienyl, where each monocyclic heterocyclic radical may optionally be substituted at any atom with one or more radicals selected from alkyl;

alkyl means a linear or branched saturated hydrocarbon radical containing from 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon radical containing from 3 to 6 carbon atoms.

This invention also relates to a compound of general formula (I), pharmaceutically acceptable acid or base addition salts thereof, stereochemical isomeric forms and oxides used as medicaments.

Further, the present invention relates to compositions containing a compound of general formula (I), pharmaceutically acceptable acid or base addition salts thereof, stereochemical isomeric forms and β-oxides, as well as to methods for preparing the compounds and compositions of the present invention.

- 5 014239

The present invention also relates to the use of a compound of general formula (I), its pharmaceutically acceptable acid or base addition salts and stereochemical isomeric forms for the manufacture of a medicament for the treatment of tachycinin-mediated conditions, in particular for the treatment and / or prevention of schizophrenia, vomiting, anxiety and depression, irritable bowel syndrome (ΕΒ8), circadian rhythm disturbances, preeclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma chronic obstructive pulmonary disease (SORE) and urinary disorders such as urinary incontinence.

DETAILED DESCRIPTION OF THE INVENTION

Preferably, this invention relates to a compound of general formula (I), its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms and Ν-oxides, wherein the spiro moiety has one of the structures below corresponding to any of the formulas (£ 6) and (£ 8), in which all variables have the same definition as in formula (I), a denotes a piperidinyl fragment of formula (I), and b denotes a fragment Л1к- ¥ -Л1к-б of formula (I)

More preferably, this invention relates to a compound of the general formula (I), its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms and Ν-oxides, wherein K. ¹ is benzyl and is attached to the 2 position as shown in the formula below compounds of formula (I) in which η and m are 1.

More preferably, this invention relates to a compound of the general formula (I), its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms and Ν-oxides, where the K ² —X — C (= 0) fragment denotes 3,5- di- (trifluoromethyl) phenylcarbonyl.

More preferably, this invention relates to a compound of general formula (I), pharmaceutically acceptable acid or base addition salts thereof, stereochemical isomeric forms and Ν-oxides, where Υ is a covalent bond or —C (═O) -.

More preferably, this invention relates to a compound of general formula (I), pharmaceutically acceptable acid or base addition salts thereof, stereochemical isomeric forms and Ν-oxides, where each A1k independently represents a covalent bond.

More preferably, this invention relates to a compound of general formula (I), its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms and β-oxides, where b is selected from the group consisting of hydrogen, tert-butyl, isopropyl, tetrahydrofuranyl, furanyl, thienyl, thiadiazolyl and pyrazinyl. Preferably b is tetrahydrofuranyl or thiadiazolyl.

More preferably, this invention relates to a compound of general formula (I), pharmaceutically acceptable acid or base addition salts thereof, stereochemical isomeric forms, Ν-oxides, where

K ² is phenyl optionally substituted with 1, 2 haloalkyl substituents;

X is a covalent bond;

O is O;

K ¹ is benzyl;

η is an integer equal to 1;

m is an integer equal to 1;

Ζ stands for covalent bond;

_), k, p, s. | denote integers independently equal to zero, 1, 2 or 3; provided that the sums (| + k) and (p + b) are 3;

ΐ denotes an integer equal to 0;

each A1k independently represents a covalent bond or a bivalent linear, saturated hydrocarbon radical containing 1 carbon atom;

- 6 014239

Υ represents a covalent bond or a bivalent radical of the formula —C (═O) -;

B is selected from the group consisting of hydrogen, alkyl, Ar ³ and He! ² ;

Ar ³ is phenyl;

Not! ² represents a monocyclic heterocyclic radical selected from the group consisting of tetrahydrofuranyl, furanyl, thienyl, thiadiazolyl and pyrazinyl; where each monocyclic heterocyclic radical may be optionally substituted at any atom with one or more alkyl radicals; and alkyl means a linear or branched saturated hydrocarbon radical containing from 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon radical containing from 3 to 6 carbon atoms.

More preferably, this invention relates to a compound of general formula (I), its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms, Ν-oxides, where the compound is a compound shown in the tables of this application, for example, in one of the tables 1-2, numbered 2-5 or 2-8.

In the context of this application, alkyl means a monovalent linear or branched saturated hydrocarbon radical containing from 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl; alkyl also means a monovalent cyclic saturated hydrocarbon radical containing from 3 to 6 carbon atoms, for example cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The definition of alkyl also includes an alkyl radical optionally substituted at one or more carbon atoms with one or more radicals selected from phenyl, halogen, cyano, oxo, hydroxy, formyl and amino, for example hydroxyalkyl, such as hydroxymethyl and hydroxyethyl, and polyhaloalkyl, such as difluoromethyl and trifluoromethyl.

In the context of this application, halogen generally refers to fluorine, chlorine, bromine and iodine.

In the context of this application, the term compounds of this invention refers to a compound of general formula (I), its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms and Ν-oxides.

In the context of this application, especially in the context of the fragment Α11 <'- Υ-Α11 < ^{Ι: ι of} formula (I), a covalent bond denoted by two or more consecutive elements refers to a single covalent bond. For example, if A1k ^a and Υ are both a covalent bond, and A1k ^b is —CH2—, then the fragment A1k ^a —U — A1k ^b is —CH2—. Similarly, if each of A1k ^a , Υ, and A1k ^b denotes a covalent bond, and b denotes H, then the APAA-AP fragment? -B denotes -H.

Pharmaceutically acceptable salts include therapeutically active non-toxic acid addition salts of the compounds of formula (I). These salts can be obtained by treating the basic form of the compound of formula (I) with suitable acids, for example inorganic acids such as hydrohalic acids, including hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.

The compounds of formula (I) containing acidic protons can be converted into therapeutically active non-toxic metal or amine addition salts by treatment with suitable organic and inorganic bases. Suitable base addition salts include, for example, ammonium salts, alkali and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium and calcium salts, organic base salts, such as benzathine, Ν-methyl-Oglucamine salts, gibramine, and salts of amino acids, for example arginine and lysine.

Conversely, these salt forms can be converted into free forms by treatment with a suitable base or a suitable acid.

The term additive salt in the context of this application also includes solvates formed by the compounds of formula (I) and their salts. Examples of such solvates are hydrates and alcoholates.

Ν-oxides of compounds of formula (I) include compounds of formula (I) in which one or more nitrogen atoms are oxidized to the so-called Ν-oxide, especially compounds in which one or more tertiary nitrogen atoms are oxidized (for example, piperazinyl radical or pyrrolidinyl). These Ν-oxides can be readily obtained by a person skilled in the art using conventional methods, and they are obviously an alternative to the compounds of formula (I), since they are metabolites formed in the human body as a result of oxidation. It is widely known that oxidation is usually the first stage in the metabolism of drugs (Tech! Looo £ Ogdashs Mebkta 1 apb Ryagtasei! 1ca1 Sjet15! Gu, 1977, Radek 70-75). It is also known that metabolites can be administered to humans instead of the compounds themselves, and often they have the same effects.

The compounds of this invention have at least two oxidizable atoms

- 7 014239 mom of nitrogen (fragments of tertiary amines). Therefore, there is a high probability that Ν’ oxides are formed as a result of metabolism in the human body.

The compounds of formula (I) can be converted to the corresponding Ν-oxides using methods known in the art for converting trivalent nitrogen to the Ν-oxide form. Said Ν-oxidation reaction is usually carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, such as sodium peroxide and potassium peroxide; suitable organic peroxides may include peroxy acids, such as benzene carboxylic acid or halogen-substituted benzene carboxylic acid, for example 3-chlorobenzene carboxylic acid, peroxyalkanoic acids, for example peroxoacetic acid, alkyl hydroperoxides, for example tert-butyl peroxides. Suitable solvents are, for example, water, lower alkanols, such as ethanol and the like, hydrocarbons, such as toluene, ketones, for example 2-butanone, halogenated hydrocarbons, for example dichloromethane, as well as mixtures of these solvents.

The term stereochemical isomeric forms in this description refers to all possible isomeric forms of the compounds of formula (I). Unless otherwise indicated or otherwise specified, the chemical name of the compound includes a mixture of all possible stereochemical isomeric forms having the same name, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More specifically, stereogenic centers may have a K or 8 configuration; substituents on bivalent cyclic (partially) saturated radicals can have either a cis or trans configuration. Compounds containing double bonds may have E or стере-stereochemistry at said double bonds. Obviously, stereochemical isomeric forms of the compounds of formula (I) are included in the scope of this invention.

If two stereogenic centers with a known absolute configuration are present in the molecule, then, in accordance with CA8 nomenclature, the chiral center with the lowest number or reference center is assigned the designation K or 8 (based on the SaiPidoI-PTEI rule). Each of K * and 8 * denotes optically pure stereogenic centers with an indefinite absolute configuration. The notations α and β are used as follows: the position of the highest priority substituent on the asymmetric carbon atom having the minimum number in the cyclic system arbitrarily designate the a-position with respect to the middle plane of the cyclic system. The position of the highest priority substituent on another asymmetric carbon atom of the cyclic system (the hydrogen atom in the compounds of formula (I)) with respect to the position of the highest priority substituent on the assignment atom is denoted by α if it is located on the same side of the mid-plane of the cyclic system, or P if it is located on the other side of the middle plane of the cyclic system.

The compounds of formula (I) and some intermediates contain at least two stereogenic centers.

Using the methods described below, the compounds of formula (I) can be synthesized as racemic mixtures of enantiomers, which can be resolved using methods known in the art. The racemic compounds of formula (I) can be converted into the corresponding diastereomeric salts by reaction with a suitable chiral acid. Then these diastereomeric salts can be separated, for example, by selective or fractional crystallization, followed by the release of enantiomers after treatment with alkali. An alternative way of separating the enantiomeric forms of a compound of formula (I) involves liquid chromatography using a chiral stationary phase. These pure stereochemical isomeric forms can also be obtained by using appropriate pure stereochemical isomeric forms as starting materials, provided that the reaction proceeds stereospecifically. If a specific stereoisomeric form is desired, said compound is preferably synthesized using stereospecific methods of preparation. In these methods, pure enantiomers are used as starting materials.

Pharmacology

Substance P and other tachykinins are involved in a number of biological functions, such as transmission of pain (nociception), inflammation of nerve tissue, smooth muscle contraction, extravasation of plasma proteins, vasodilation, secretion, mast cell degranulation, as well as activation of the immune system. It is believed that a number of diseases are mediated by activation of neurokinin receptors, in particular ΝΚ receptor, as a result of increased release of substance P and other neurokinins by specific cells, such as cells of the neuronal network of the gastrointestinal tract, non-myelinated primary sensory afferent neurons, sympathetic and parasympathetic neurons, as well as other than neurons of the cell (ΌΝ & Ρ 8 (1): 5-23 (1995) aib Lidogt 1. c1 a1., No. KeserFga Riattacoodua1 Xu1C \\ b 46 (4): 551-599 (1994)).

The compounds of the present invention are effective inhibitors of neurokinin-mediated effects, in particular, receptor- ₁ mediated effects, and therefore can be considered antagonists of neurokinins, especially antagonists of substance P, which is confirmed

- 8 014239 by suppressing ίη νίΐτο by the substance P-induced relaxation of pig coronary arteries. The affinity of binding of the compounds of the present invention to receptors of human neurokinins, guinea pigs and gerbils can also be determined ίη νίΐτο by analysis of receptor binding using ³ H-substance P as a radioligand. The tested compounds also exhibit antagonistic activity with respect to the substance P ίη νίνο, which is confirmed, for example, by the suppression of the extravasation of plasma proteins induced by the substance P in guinea pigs, or the suppression of drug-induced vomiting in ferrets (\ Va150p c1 a1., Br. 1. Rjatshaso1 115: 84-94 (1995)).

Due to their ability to suppress the action of tachykinins by blocking neurokinin receptors, especially receptor ΝΚ ₁ , the compounds of this invention can be used as a medicine, for example, for the prevention and treatment of tachycinin-mediated conditions. In particular, for the prevention and treatment of tachycinin-mediated conditions, the compounds of this invention can be used as drugs having oral activity and are able to penetrate the central nervous system.

Therefore, this invention relates to the use of a compound of general formula (I), its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms, Ν-oxides, and also their prodrugs, as a medicine.

The present invention also relates to the use of a compound of general formula (I), its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms, oxides, and also their prodrugs, for the manufacture of a medicament for the prevention and / or treatment of tachycinin-mediated conditions.

The compounds of this invention can be used to treat CNS disorders, such as schizoaffective disorders; depression; anxiety disorders; stress-related disorders; sleep disturbances; cognitive impairment; personality disorders; eating disorders; neurodegenerative diseases; addiction disorders; mood disorders; sexual dysfunction; visceral pain and other conditions associated with disorders of the central nervous system; inflammation allergic disorders; vomiting gastrointestinal disorders such as irritable bowel syndrome (1B8); skin diseases; vasospastic diseases; fibrotic and collagen diseases; disorders related to the strengthening or suppression of immunity; rheumatic diseases; as well as for the regulation of body weight.

In particular, the compounds of this invention can be used to treat or prevent schizoaffective disorders of various etiologies, including schizoaffective disorders of the manic type, depressive type and mixed type; paranoid, disorganizing, catatonic, undifferentiated and residual schizophrenia; schizophrenia-like disorder; hallucinatory disorder; brief mental disorder; general mental disorder; mental illness caused by a substance; as well as other mental disorders.

In particular, the compounds of this invention can be used to treat or prevent depression, including, without limitation, major depressive disorders, such as bipolar depression; monopolar depression; single or recurring attacks of major depression, sometimes accompanied by psychotic symptoms, catatonic signs, melancholic symptoms, atypical symptoms or postnatal appearance, and repeated attacks may be seasonal in nature. Other mental disorders covered by the term major depressive disorder include dysthymic disorder with an early or late onset, sometimes accompanied by atypical symptoms; bipolar disorder I; bipolar disorder II; cyclothymic disorder; recurrent short depressive disorder; mixed affective disorder; neurotic depression; violation associated with post-traumatic stress, and sociophobia; early or late dementia of the Alzheimer's type, accompanied by a depressed mood; substance-induced mood disorders, such as mood disorders caused by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressive type; and adaptive disorder with a depressive mood. Major depressive disorders can also occur as a result of a general medical condition, including, without limitation, myocardial infarction, diabetes, termination of pregnancy or abortion, etc.

In particular, the compounds of this invention can be used to treat or prevent anxiety disorders, including, without limitation, an attack of panic disorder; agoraphobia; panic disorder without agoraphobia; agoraphobia without panic disorder; specific phobia; social phobia; obsessive-compulsive disorder; disturbance associated with post-traumatic stress; associated with acute stress; generalized anxiety disorder; anxiety disorder due to a general medical condition; substance-induced anxiety disorder; as well as other anxiety disorders.

In particular, the compounds of this invention can be used to treat or prevent stress-related disorders associated with depression and / or anxiety, including, without ogre

- 9 014239 nitseniya, acute stress reaction; adaptation disorders such as a brief depressive reaction and a prolonged depressive reaction; mixed anxiety and depressive reactions; violation of the device with a dominant violation of other emotions; violation of the device with a dominant violation of behavior; violation of the device with a mixed violation of emotions and behavior; disorders of the device with the dominance of other symptoms; as well as other reactions to severe stress.

In particular, the compounds of this invention can be used to treat or prevent sleep disorders, including, but not limited to, dysomnia and / or parasomnia as primary sleep disorders; insomnia sleep apnea / narcolepsy; circadian rhythm disturbances; sleep disorders associated with another mental illness; sleep disturbance due to a general medical condition; as well as sleep disturbance induced by the substance.

In particular, the compounds of this invention can be used to treat or prevent cognitive impairment, including but not limited to dementia; amnestic disorders and other cognitive disorders, in particular dementia caused by degenerative disorders, injuries, trauma, infections, vascular diseases, toxins, anoxia, vitamin deficiency or endocrine diseases; early or late dementia of the Alzheimer's type, sometimes with a depressed mood; AIDS-related dementia or amnestic disorders caused by alcohol or other causes, including thiamine deficiency, bilateral damage to the temporal lobe due to herpetic encephalitis and other limbic encephalitis, a decrease in the number of neurons after anoxia / hypoglycemia / severe convulsions and surgery, degenerative disorders, vascular disorders or pathology in the area of the ventricle III. In addition, the compounds of this invention can also be used as agents that improve memory and / or cognitive ability in healthy people who do not suffer from a deficit in cognitive ability and / or memory.

In particular, the compounds of this invention can be used to treat or prevent personality disorders, including, without limitation, paranoid personality disorder; schizoid personality disorder; schizophrenic personality disorder; antisocial personality disorder; borderline personality violation; facial personality disorder; narcissistic personality disorder; personality disorder associated with closed behavior; personality disorder related to addiction; obsessive-compulsive personality disorder, as well as other personality disorders.

In particular, the compounds of this invention can also be used for the treatment or prevention of eating disorders, including anorexia nervosa; atypical anorexia nervosa; bulimia neurogenic; atypical neurogenic bulimia; overeating associated with other psychological disorders; vomiting associated with other psychological disorders; and non-specific eating disorders.

In particular, the compounds of this invention can also be used to treat or prevent neurodegenerative diseases, including, but not limited to, Alzheimer's disease; Huntington's chorea; Creutzfeldt-Jakob disease; Peak's disease; demyelinating diseases such as multiple sclerosis and AB8; other neuropathies and neuralgia; multiple sclerosis; amyotrophic lateral sclerosis; stroke and head injury.

In particular, the compounds of this invention can also be used to treat or prevent addiction disorders, including, without limitation, addiction, sometimes physiological, to substances, or abuse of substances, especially when the substance is alcohol, amphetamines , amphetamine-like substances, caffeine, cocaine, hallucinogens, inhalants, nicotine, opioids (such as cannabis, heroin and morphine), phencyclidine, phencyclidine-like compounds, sedative-hypnotic agents , benzodiazepines and / or other substances, especially those used to treat withdrawal symptoms resulting from the withdrawal of the above substances, and delirious syndrome after withdrawal of alcohol.

In particular, the compounds of this invention can also be used to treat or prevent mood disorders, in particular those caused by alcohol, amphetamines, caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances.

In particular, the compounds of this invention can also be used to treat or prevent sexual dysfunction, including but not limited to impaired sexual desire; disturbances in sexual arousal; orgasmic disturbances; sexual pain disorders; sexual dysfunction due to a general medical condition; substance-induced sexual dysfunction, as well as other sexual dysfunctions.

In particular, the compounds of this invention can also be used to treat or prevent pain, including, without limitation, traumatic pain, such as postoperative pain; pain associated with traumatic rupture, such as shoulder grip; chronic pain, such as arthritic pain, for example, occurring in osteorheumatoid or psoriatic

- 10 014239 arthritis; neuropathic pain, such as postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-related neuropathy, AIDS neuropathy, neuralgia colral neuralgia, neuralgia, neuralgia sympathetic reflex dystrophy and phantom pains; various forms of headache, such as migraine, acute or chronic pain with high blood pressure, temporomandibular pain, maxillary sinus pain and severe paroxysmal headache; odontalgia; cancer pain visceral pain; gastrointestinal pain; pain when the nerve is pinched; pain from sports injuries; pain with dysmenorrhea; menstrual pain; pain with meningitis; pain with arachnoiditis; musculoskeletal pain; pain in the lower back, for example, with vertebral stenosis, prolapsed disc, sciatica, angina pectoris, ankylosing spondylitis; gout pain; burn pain; scar pain; itching and thalamic pain, such as thalamic pain after a stroke.

In particular, the compounds of this invention can also be used for the treatment or prevention of other conditions related to the central nervous system, such as: akinesia, akinetic resistant syndromes, dyskinesia and parkinsonism caused by drugs, Syndrome syndrome and its symptoms, tremor, chorea, myoclonia , tic and dystonia, attention deficit / hyperactivity disorder (ΆΌΗΌ), Parkinson's disease, drug-induced parkinsonism, postencephalitis parkinsonism, progressive supranuclear p aralich, multiple atrophy, corticobasal degeneration, complex dementia associated with Parkinsonism-AB8, and calcification of the basal nuclei of the brain, behavioral disorders and behavioral disorders in dementia and mental retardation, including anxiety and anxiety, disturbances of extrapyramidal motor functions, Down syndrome and akathisia.

In particular, the compounds of this invention can also be used to treat or prevent inflammation, including, without limitation, inflammatory conditions in asthma, influenza, chronic bronchitis and rheumatoid arthritis; inflammatory conditions in the gastrointestinal tract, including, without limitation, Crohn’s disease, ulcerative colitis, inflammatory bowel disease and damage caused by a non-steroidal anti-inflammatory agent; inflammatory skin conditions such as herpes and eczema; bladder inflammatory conditions such as cystitis and urgent urinary incontinence; inflammation of the eyes and teeth and pancreatitis, including chronic and acute pancreatitis.

In particular, the compounds of this invention can also be used to treat or prevent allergic diseases, including, but not limited to, allergic skin diseases such as urticaria; and allergic respiratory diseases such as rhinitis.

In particular, the compounds of the present invention can also be used to treat or prevent vomiting, i.e., nausea, retching and vomiting, including, but not limited to, acute vomiting, delayed vomiting, and premature vomiting; vomiting caused by factors such as drugs, including anti-cancer chemotherapeutic agents, such as alkylating agents, for example cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics such as dactinomycin, doxorubicin, mitomycin-C and bleomycin; antimetabolites such as cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids such as etoposide, vinblastine and vincristine; as well as other drugs, such as cisplatin, dacarbazine, procarbazine and hydroxyurea; as well as their combinations; radiation sickness; radiation therapy, for example, used to treat cancer; poisons toxins, such as toxins resulting from metabolic disorders or infections, such as gastritis, or released during a bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness, and Meniere's disease; postoperative nausea; blockage of the gastrointestinal tract; decreased motor function of the gastrointestinal tract; visceral pain, for example, with myocardial infarction or peritonitis; migraine; increased intracranial pressure; decreased intracranial pressure (for example, altitude sickness); opioid analgesics such as morphine; gastroesophageal outflow; heartburn; excessive consumption of food or drink; sour stomach; sour belching; heartburn / belching; heartburn, such as episodic heartburn, nocturnal heartburn and heartburn caused by food; and dyspepsia.

In particular, the compounds of this invention can also be used to treat or prevent gastrointestinal upsets, including, but not limited to, irritable bowel syndrome (ΙΒ8), skin diseases such as psoriasis, pruritus, and sunburn; vasospastic diseases such as angina pectoris, vascular headache and Raynaud's disease, cerebral ischemia, such as cerebral vasospasm after subarachnoid bleeding; fibrotic and collagen diseases, such as scleroderma and eosinophilic fascioliasis; diseases associated with enhancing or suppressing immunity, such as systemic lupus erythematosus and rheumatic diseases, such as fibrositis; cough; as well as dysregulation of body weight, including obesity.

The compounds of this invention can also be used to obtain a medicinal product for the treatment and / or prevention of schizophrenia, vomiting, anxiety and depression, irritable syndrome

- 11 014239 intestines (ΙΒ8), circadian rhythm disturbances, preeclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (SORI), and urinary disorders such as urinary incontinence.

The present invention also relates to a method for the treatment and / or prevention of schizophrenia, vomiting, anxiety and depression, irritable bowel syndrome (ΙΒ8), circadian rhythm disturbances, preeclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma chronic obstructive pulmonary disease (SORE) and urination disorders such as urinary incontinence, including the administration to a person in need of such administration, an effective amount of a compound of this invention, in particular, compounds of the formula (Ι), its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms, Ν-oxides, and also their prodrugs.

The present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound of this invention, in particular a compound of formula (Ι), its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms, Ν -oxides and prodrugs.

The compounds of this invention, in particular the compounds of formula (I), their pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms, Ν-oxides and prodrugs, or any combination thereof, may be included in various pharmaceutical forms for administration. As suitable compositions, any compositions commonly used for systemically administering drugs can be listed. In order to obtain the pharmaceutical compositions of the present invention, an effective amount of a particular compound, optionally in the form of an additive salt, is combined as an active ingredient by uniform mixing with a pharmaceutically acceptable carrier, which may take different forms depending on the type of preparation to be administered. Preferably, these pharmaceutical compositions are in unit dosage forms suitable, for example, for administration by the oral, rectal, transdermal route, by parenteral injection or by inhalation. For example, to obtain compositions in the form of an oral dosage form, you can use any traditional pharmaceutical medium, such as, for example, water, glycols, oils, alcohols, etc. in the case of liquid preparations for oral administration, such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like, in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules are the most preferred unit dosage forms for which solid pharmaceutical carriers are naturally employed. In parenteral compositions, the carrier usually contains sterile water, at least in the main part, although it may contain other ingredients, for example, increasing the solubility of drugs. Injectable solutions, for example, as a carrier may contain saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may contain suitable liquid carriers, suspending agents, and the like. Solid preparations are also included in the scope of the present invention, which must be converted to liquid preparations immediately before use. In compositions suitable for transdermal administration, the carrier optionally contains a penetration enhancing agent and / or a suitable moisturizer, optionally in combination with suitable additives of any nature in minor proportions that do not have a significant harmful effect on the skin. These additives may facilitate the administration to the skin and / or the preparation of the desired compositions. These compositions can be administered in various ways, for example, using a transdermal patch, spot-on application, or ointment.

It is particularly preferable to obtain the above pharmaceutical compositions in the form of a unit dosage form providing ease of administration and uniformity of dosage. The term unit dosage form, as used herein, refers to physically discrete units that can be used as unit doses, each of which contains a certain amount of active ingredient, calculated to provide the desired therapeutic effect, in combination with a suitable pharmaceutical carrier. Examples of such unit dosage forms are tablets (including notched tablets or coated tablets), capsules, pills, powder sachets, cachets, suppositories, injectable solutions or suspensions, etc., as well as their separate parts.

Since the compounds of this invention are antagonists of ΝΚ having activity, mainly in the central nervous system, after oral administration, pharmaceutical compositions of these compounds for oral administration are particularly preferred.

Synthesis

The compounds of this invention can generally be obtained using a sequence of steps, each of which is known to those skilled in the art.

- 12 014239

The final compounds of formula (1a) are usually prepared by reductive Ν-alkylation of an intermediate of formula (II) with an intermediate of formula (III). Said reductive Ν-alkylation can be carried out in an inert solvent, such as, for example, dichloromethane, ethanol or toluene, or a mixture thereof, in the presence of a suitable reducing agent, such as borohydride, for example sodium borohydride, sodium cyanoborohydride or triacetoxyborohydride. If borohydride is used as a reducing agent, it is preferable to use a complexing agent with it, such as, for example, titanium (IV) isopropylate, as described in I. Ogd. Oh. 1990, 55, 2552-2554. The use of said complexing agent can lead to a shift in the cis / trans ratio towards the trans isomer. Hydrogen can also be used as a reducing agent in combination with a suitable catalyst, such as, for example, palladium on carbon or platinum on coal. In the case of using hydrogen as a reducing agent, a dehydrating agent, such as, for example, aluminum tert-butoxide, can be added to the reaction mixture. To prevent undesired hydrogenation of certain functional groups of reactants and reaction products, a suitable catalyst poison, for example thiophene or quinoline-sulfur, can also be added to the reaction mixture. The reaction rate can be increased by stirring and optionally by applying elevated temperatures and / or pressure.

In this and subsequent methods, reaction products can be isolated from the reaction medium and, if necessary, further purified using methods well known in the art, such as, for example, extraction, crystallization, trituration and chromatography.

The final compounds of formula (4b) are usually prepared by reductive алки -alkylation of an intermediate of formula (IV) with an intermediate of formula (III). Said reductive Ν-alkylation can be carried out in an inert solvent, such as, for example, dichloromethane, ethanol or toluene, or a mixture thereof, in the presence of a suitable reducing agent, such as borohydride, for example sodium borohydride, sodium cyanoborohydride or triacetoxyborohydride. If borohydride is used as a reducing agent, it is preferable to use a complexing agent with it, such as, for example, titanium isopropylate (U), as described in I. Ogd. SN, 1990, 55, 2552-2554. Hydrogen can also be used as a reducing agent in combination with a suitable catalyst, such as, for example, palladium on carbon or platinum on coal. In the case of using hydrogen as a reducing agent, a dehydrating agent, such as, for example, aluminum tert-butoxide, can be added to the reaction mixture. To prevent undesired hydrogenation of certain functional groups of reactants and reaction products, a suitable catalyst poison, for example thiophene or quinoline-sulfur, can also be added to the reaction mixture. The reaction rate can be increased by stirring and optionally by applying elevated temperatures and / or pressure.

The final compounds of formula (K) are usually prepared by reacting a compound of formula (V) as a carboxylic acid with an intermediate of formula (III). The reaction can be carried out in an inert solvent, such as a chlorinated hydrocarbon, for example dichloromethane, in the presence of a suitable base, such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine, as well as in the presence of an activator, such as, for example, BSS (dicyclohexylcarbodiimide), SB ! (carbonyldiimidazole) and EBL (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-HC1). The reaction rate can be increased by stirring. The reaction is usually carried out in the temperature range from room temperature to the boiling point under reflux.

- 13 014239

In a particularly preferred method for preparing the final compound of any of the formulas Yes), D) and De), carried out in accordance with the above reaction schemes, the compound of formula (II), (IV) or (V) is reacted with a compound of formula (III) in wherein the A1k-Y-A1k-b fragment is benzyl (formula (XI)) to form a compound in which the A1k-¥ -A1k-b fragment is benzyl. The specified final compound is pharmacologically active and can be converted into the final compound of formula (I '), in which the fragment A1k-Y-A1k-b represents hydrogen, by reductive hydrogenation using, for example, hydrogen as a reducing agent in combination with a suitable a catalyst, such as, for example, palladium on charcoal or platinum on charcoal. Then, the resulting final compound of this invention can be converted into other compounds of formula (I) by reactions known in the art, for example, acylation and alkylation.

((I) OR (IV) or ⁺ (V)

ΗΝ U Ν-benzyl \ sn & 1sn ₂ {,

P ¹

but. / \ - (cn ₂ ) _t / ^CH ^ 1 ^CH ^, (T),

7 “N 'U-Ζ — Ν U ΝΗ _r g_x (XI) (D)

In particular, the final compounds of formula (I) can be obtained by reacting the final compound of formula (I ') with an intermediate of formula (VI), in which XV ¹ represents a suitable leaving group, such as halogen, for example chlorine or bromine, or sulfonyloxy leaving a group, for example methanesulfonyloxy or benzenesulfonyloxy. The reaction can be carried out in an inert solvent, such as a chlorinated hydrocarbon, for example dichloromethane, or a ketone, for example methyl isobutyl ketone, in the presence of a suitable base, such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. The reaction rate can be increased by stirring. The reaction is usually carried out in the temperature range from room temperature to the boiling point under reflux.

Alternatively, the final compounds of formula (I) can be prepared by reacting the final compound of formula (I ') with a carboxylic acid of formula (VII). The reaction can be carried out in an inert solvent, such as, for example, a chlorinated hydrocarbon, for example dichloromethane, in the presence of a suitable base, such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine, in the presence of an activator, such as, for example, OCC (dicyclohexylcarbodiimide), SE! (carbonyldiimidazole) and ΕΌΟ (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-HC1). The reaction rate can be increased by stirring. The reaction is usually carried out in the temperature range from room temperature to the boiling point under reflux.

The final compounds of formula (1e) can be obtained by alkylating the final compound of formula (I ') with a compound of formula (VIII) in which V ² is a suitable leaving group, such as, for example, halogen, for example chlorine or bromine, or a sulfonyloxy leaving group, for example methanesulfonyloxy or benzenesulfonyloxy. The reaction can be carried out in an inert solvent, such as a chlorinated hydrocarbon, for example dichloromethane, an alcohol, for example ethanol, or a ketone, for example methyl isobutyl ketone, in the presence of a suitable base, such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. The reaction rate can be increased.

- 14 014239 by stirring. The reaction is usually carried out in the temperature range from room temperature to the boiling point under reflux.

^{1 1} / / ^(a ° ° ^ cn.

Αν 'Y-ζ - ν Υ W + HH ρ? -Χ HhH,

K ¹ about

Α ^Ν 'ζ- ν Υ Ν-ж-и κ®-χ - (led, Ш.Ы, (Г) (VIII) (those)

The final compounds of formula (I) are usually prepared by reductive Ν-alkylation of an intermediate of formula (I ') with an intermediate of formula (IX). Said reductive Ν-alkylation can be carried out in an inert solvent, such as, for example, dichloromethane, ethanol or toluene, or a mixture thereof, in the presence of a suitable reducing agent, such as borohydride, for example sodium borohydride, sodium cyanoborohydride or triacetoxyborohydride. If borohydride is used as a reducing agent, it is preferable to use a complexing agent with it, such as, for example, titanium (IV) isopropylate, as described in I. Ogd. SNSSh. 1990, 55, 2552-2554. Hydrogen can also be used as a reducing agent in combination with a suitable catalyst, such as, for example, palladium on carbon or platinum on coal. In the case of using hydrogen as a reducing agent, a dehydrating agent, such as, for example, aluminum tert-butoxide, can be added to the reaction mixture. To prevent undesired hydrogenation of certain functional groups of reactants and reaction products, a suitable catalyst poison, for example thiophene or quinoline-sulfur, can also be added to the reaction mixture. The reaction rate can be increased by stirring and optionally by applying elevated temperatures and / or pressure.

I ¹ a L (CHa) _t

7— N ¹ Α ^Ζ- “ ^!

Ρΐ ² —X - (СУЛ (С> А (Снк * Чсна, кААйо

The final compounds of formula (1e) are usually prepared by the Mannich boronic reaction described in Te1gayebgop, 1997, 53, 16463-16470; I. At. Oh. §Os. 1998, 120, 11798-11799 or Te1gayebgop Le11eg8, 2002, 43, 5965-5968, in which the intermediate of formula (I ') and the intermediates (X) and (XI) are involved, where Υ in the formula (X) is bivalent a radical of the formula CH ₂ - or> C (= O), and V ³ in the formula (XI) is hydrogen or an alkyl chain. Said Mannich boronic reaction can be carried out in a single vessel in the presence of a carbohydrate or its dimer of formula (X) and an arylboronic acid or arylboronic acid ester of formula (XI) in an inert solvent such as, for example, dichloromethane, ethanol or 2,2,2-trifluoroethanol , or a mixture thereof. The reaction rate can be increased by stirring. The reaction is usually carried out in the temperature range from room temperature to the boiling point under reflux.

(D) (X) (XI) 0th

The following examples are intended to illustrate, but not to limit the scope of the present invention.

experimental part

In this description, HOBT refers to hydroxybenzotriazole, EEST ¹ refers to 1ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and POCC refers to a dicyclohexylcarbodiimide polymer.

Preparation of Intermediates

Example A1

but. Preparation of Intermediate 1

- 15 014239 with stirring to a mixture of 7- (phenylmethyl) -1,4-dioxo-81 hours add 3,5-

with toluene (1500 ml). During

Εΐ ₃ Ν (0.55 mol) add azaspiro [4.5] decane (0.5 mol) to bis (trifluoromethyl) benzoyl chloride (0.5 mol) (exothermic reaction). The mixture was stirred at room temperature for 2 hours, then left to stand over the weekend and washed three times with water (500 ml, 2x250 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. Yield: 245 g (100%). After crystallization of 2 g of this fraction from petroleum ether, 1 g of intermediate 1 (50%) is obtained.

B. Preparation of Intermediate 2

To a mixture of intermediate 1 (0.5 mol) in ethanol (300 ml) and H ₂ O (300 ml) was added HCl (300 ml). The reaction mixture was stirred at 60 ° C for 20 hours. The precipitate was filtered off, milled, stirred in Н2О, filtered again, washed with petroleum ether and dried. Yield: 192 g of intermediate 2 ((±) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (phenylmethyl) -4 piperidinone) (89.4%) (mixture of K- and 8-enantiomers).

from. Preparation of Intermediate 3 and Intermediate 4

Intermediate 2 was separated into optical isomers by chiral column chromatography on a Syga1rak column (SCHKRAK A8 1000A 20 mm (ΌΑΚΈΕ); eluent: hexane / 2 propanol 70/30). Two fractions of the product are collected and all solvents are evaporated. The yield for fraction 1: 32.6 g of intermediate 3 (K), and for fraction 2: 30.4 g of intermediate 4 (8).

Example A2.

but. Preparation of Intermediate 5

A mixture of [1- (phenylmethyl) -3-pyrrolidinylidene] acetic acid ethyl ester (0.071 mol) (obtained by the method described in European patent EP 550025 A1, the contents of which are fully incorporated into this description by reference), 0Η ₃ ΝΟ ₂ ( 170 ml) and Ν, Ν, Ν ', Ν' tetramethylguanidine (3 ml) were stirred and refluxed for 18 hours. Η ₂ Ο was added. The mixture was extracted, washed with CH ₂ Cl ₂ and concentrated to give 15 g. The residue was purified by silica gel column chromatography (using a gradient of CH ₂ Cl ₂ / MeOH from 100/0 to 99/1; 15-40 μm as eluent). Pure fractions were collected and the solvent was evaporated. Yield: 4.7 g of intermediate 5 (21%).

B. Preparation of Intermediate 6

A mixture of intermediate compound 5 (obtained by the method of example A2.a) (0.027 mol) and Κ, αΝί

- 16 014239 (8 g) in MeONJS (80 ml) was hydrogenated at room temperature and a pressure of 3 bar for 18 hours. The mixture was filtered through celite, washed with MeOH / CH ₂ Cl ₂ and concentrated. The residue is crystallized from ESAc. getting 2.4 g (38%) of fraction 1. The mother liquor is evaporated. The residue (5.3 g) was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / MeOH 98/2; 20-45 μm). Pure fractions were collected and 1.3 g of fraction 2 was obtained. Fraction 1 and fraction 2 were combined to obtain 3.7 g of intermediate 6 (59%).

from. Preparation of Intermediate 7

Intermediate 6 (0.016 mol) was added portionwise at 5 ° C. to a solution of L1A1H ₄ (0.032 mol) in THE (75 ml). The mixture was stirred at room temperature for 18 hours. H ₂ O was slowly added at 5 ° C. The mixture was filtered through celite, washed with EyAc and CH ₂ Cl ₂ , dried over MgSO ₄ , filtered, dried and concentrated. Yield: 3.3 g of intermediate 7 (95%).

Obtaining the final compounds

Example B1

but. Getting the final connection 1-2

A mixture of intermediate 3 (obtained by the method of example A1.c) (0.028 mol), 1 (phenylmethyl) -1,7-diazaspiro [4.4] nonane (0.028 mol), Ρά / C (1 g) and titanium (IV) isopropylate (0.033 mol) in thiophene (1 ml) and CH3OH (120 ml) are hydrogenated at 50 ° C for 18 hours, then filtered through celite. Celite is washed with CH ₃ OH. The filtrate was evaporated. The residue was dissolved in CH ₂ Cl ₂ . Add 10% To ₂ CO ₃ . The mixture was stirred at room temperature for 30 minutes, then filtered through celite. Celite is washed with CH ₂ Cl ₂ . The filtrate was extracted with CH ₂ Cl ₂ . The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (a gradient was used as an eluent: CH ₂ Cl ₂ / CH ₃ OH / XH ₄ OH from 98/2 / 0.2 to 97/3 / 0.2; 20-45 μm). Pure fractions were collected and the solvent was evaporated, yielding 4.9 g of fraction 1 and 2.7 g of fraction 2. Yield: 0.113 g of final compound 1-2.

B. Obtaining the final compound 1-1

A mixture of the final compound 1-2 (0.004 mol) and Ρά / C (1 g) in CH ₃ OH (15 ml) was hydrogenated at 50 ° C for 18 h under a pressure of 3 bar, and then filtered through celite. Celite is washed with CH ₂ Cl ₂ / CH ₃ OH. The filtrate was evaporated. Yield: 2.3 g of final compound 1-1 (100%).

Example B2. Getting the final connection 1-3

ΕΌΟ (0.001 mol) is added at room temperature to a solution of the final compound 1-1 (obtained by the method of Example B1. L) (0.001 mol), cyclopropanecarboxylic acid (0.001 mol), NEW! (0.001 mol) and Εΐ ₃ Ν (0.001 mol) in CH ₂ Cl ₂ (4 ml). The mixture is stirred at room temperature.

- 17 014239 for 18 hours. The organic layer was washed with 10% K ₂ CO ₃ , dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue (0.5 g) was purified by silica gel column chromatography (the gradient was used as an eluent: CH ₂ Cl ₂ / CH ₃ OH from 99/1 to 80/20; 5 μm). Pure fractions were collected and the solvent was evaporated. Yield: 0.22 g of final compound 1-3.

Example B3

but. Obtaining the final compound 2-1

A mixture of intermediate compound 3 (obtained by the method of example A1.c) (0.015 mol), intermediate 7 (obtained by the method of example A2.c) (0.015 mol), titanium isopropylate (1U) (0.023 mol), thiophene (0.6 ml) and Pb / C (0.6 g) in MeOH (60 ml) are hydrogenated at 50 ° C under a pressure of 3 bar for 18 hours. The mixture is filtered through celite, washed with MeOH and concentrated to dryness. The residue was solubilized in CH ₂ Cl ₂ , 10% K ₂ CO _{3 was} added, the mixture was stirred at room temperature for 30 minutes, filtered through celite, washed with CH ₂ Cl ₂ . The filtrate was extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , filtered and concentrated. The residue (8.7 g) was purified by silica gel column chromatography (the gradient was used as an eluent: CH ₂ Cl ₂ / MeOH / YAN ₄ OH from 98/2 / 0.2 to 95/5 / 0.2; 15-40 μm ) Yield: 0.9 g of final compound 2-1.

B. Obtaining the final compound 2-2

A mixture of final compound 2-1 (obtained by the method of Example B3.a) (0.001 mol) and Pb / C (0.1 g) in MeOH (10 ml) was hydrogenated under a pressure of 3 bar for 18 hours at room temperature. The mixture was filtered through celite, washed with CH ₂ Cl ₂ / MeOH and concentrated. Yield: 0.8 g of final compound 2-2 (100%).

Example B4 Obtaining the final compound 2-4

A mixture of final compound 2-2 (obtained by the method of Example B3.b) of cyclopropanecarboxylic acid (1.2 equivalents) and cyclohexylcarbodiimide immobilized on a polymer (1.2 equivalents) in CH2C12 was stirred at room temperature for 18 hours. Yield: 45% of the final compounds 2-4.

The following compounds are prepared according to the method of one of the above examples.

Table 1

- 18 014239

Connection No. Example No. A1k V AH? b Stereoisomer designation 1-1 B1.j bj b b n 2K-trans 1-2 B1.a -sn - b b BUT 2Я-trans 1-3 AT 2 bj with b % 2K-trans 1-4 AT 2 bj with bj 2H-CIS 1-5 AT 2 bj with b BUT 2K-trans 1-6 AT 2 b with bj BUT 2Я-ЦИС 1-7 AT 2 bj c = o b BUT 2Я-trans 1-8 AT 2 b with b BUT 2D-CIS one-? AT 2 bj with bj BUT 2K.-CIS yo AT 2 bj with b BUT 2nd trance 1-11 AT 2 b with b BUT 2K-CIS 1-12 AT 2 b with b BUT N 2K.-C18

cb: covalent bond

- 19 014239

table 2

Connection No. Example No. A1k * Υ A11? B Stereo designation; isomer ¹ 2-1 vz b bj b n 2B-trans 2-2 VZ.a -SNg bj b h 2K, -trans 2-3 AT 4 bj C = O b 2K-trans 2-4 AT 4 b c = o bj <7 2K-trans 2-5 AT 4 bj c = o bj 2K-trans 2-6 AT 4 b c = o b h 2K-trais 2-7 AT 4 bj c = o b g * h 2K-trans 2-8 AT 4 b with b 2K-trans

2-9 AT 4 bj C = O b 2Я-trans 2-10 AT 4 bj C = O b 211-trans

cb: covalent bond

C. Analytical evidence

Some compounds are analyzed by LC-MS and NMR.

C.1 LC-MS conditions

General way:

To perform gradient HPLC, the AShais NT 2795 (^ a1etk) system is used, consisting of a quaternary pump with a degasser, an autosampler and a detector ΌΑΌ. Part of the flow exiting the column is directed to the MS detector. MS detectors are equipped with an electrospray ionization device. The voltage of the capillary needle is 3 kV, the temperature of the source is maintained at 100 ° C. Nitrogen is used as atomizing gas. Data are obtained using the \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\:: :S.

Method 1

In addition to the general procedure: reverse phase HPLC was performed on a Ktotaky C18 column (5 μm, 4.6x150 mm) at a flow rate of 1 ml / min. Two mobile phases (mobile phase A: 100% 6.5 mM ammonium acetate + 0.2% formic acid; mobile phase B: 100% acetonitrile) are used to obtain the following gradient: from 60% A and 40% B for 1 min , to 100% B for 4 minutes, from 100% B for 5 minutes, to 60% A and 40% B for 3 minutes, with re-balancing with a mixture of 60% A and

- 20 014239

40% B for 3 minutes The injection volume is 5 μl. The cone voltage is 20 V for positive ionization mode. The mass spectrum is obtained by scanning from 100 to 900 for 1 s using a holding time of 0.1 s.

Method 2

In addition to the general procedure: reverse phase HPLC was carried out on an X1egga-BP C18 column (5 μm, 3.9 x 150 mm) with a flow rate of 1.0 ml / min. Two mobile phases (mobile phase A: 100% 7 mm ammonium acetate; mobile phase B: 100% acetonitrile) are used to obtain the following gradient: from 85% A, 5% B (within 3 min) to 20% A, 80% B for 5 minutes, 20% A and 80% B were maintained for 6 minutes and again balanced under initial conditions for 3 minutes. The injection volume is 20 μl. The cone voltage is 20 V for positive ionization mode. The mass spectrum is obtained by scanning from 100 to 900 for 0.8 s using a delay time of 0.08 s.

Table 3. LC-MS results for individual compounds; main peak and retention time

No. connections LC-MS, MS (MH +) Retention time Way 1-2 630 12.03 2 1-3 608 4.90 one 1-4 608 5.20 one *-5 638 4.60 one 1-6 638 4.66 one 1-7 634 4.96 one 1-8 634 5.14 one 1-9 650 5.27 one 1-10 644 5.17 I 1-11 644 5.40 one 1-12 646 4.76 one 2-3 624 5.21 one 2-4 608 4.74 one 2-5 638 4.36 one 2-6 634 4.84 one

2-7 650 4.97 one 2-8 666 4.88 one 2-9 644 5.06 one 2-10 646 4.50 one

C. 2. Conditions for NMR

The proton NMR spectrum is recorded on Vgikeg Auaps 400 spectrometers (400 MHz) using deuterium as an internal standard. Chemical shifts are given relative to the internal DMSO (δ 2.54) in ppm (parts per million), and the interaction constants (I) in Hz.

Compound No. 1-1: Ή NMR (EM8O-b ₆ ) δ 1.2-2.05 (11H, m), 2.5-3.05 (8H, m), 3.2-5.1 (4H , m) 6.8-8.2 (8H, m).

Ό. Pharmacological Example

Example No. 1: Analysis of the binding of receptors y-ΝΚι, 1ι-ΝΚ _; and 1ι-ΝΚ ₃

The interaction of the compounds of this invention with receptors involved in nerve signal transmission, ion channels and transport protein binding sites is analyzed by radioligand binding method. Membranes of tissue homogenates or cells expressing a receptor or transport protein of interest are incubated with a radiolabeled substance ([ ³ H] - or [ ¹²⁵ 1] ligand) interacting with a particular receptor. The specific binding of the radiolabeled ligand to the receptor is distinguished from non-specific binding to the membrane by selective

- 21 014239 inhibition of labeling of the receptor with an unlabeled substance (blank), which is known to compete with the radioligand for binding to the receptor. After incubation, the labeled membranes are collected, washed with an excess of cold buffer and the unbound radioactive label is removed by rapid filtration under vacuum. Membrane-bound radioactivity is counted using a scintillation counter and results are obtained in the form of the number of pulses per minute (cf.).

Compounds are dissolved in DMSO, yielding 10 different concentrations in the range from 10 ^-10 to 10 ^-5 M.

Analyze the ability of the compounds of this invention to replace the [ ³ H] substance P upon binding to the cloned human L-ΝΚμ receptor expressed in CHO cells, to replace [ ³ H] -8K-48968 upon binding to the cloned human receptor 1ι-ΝΙ <2. expressed in 8 £ 9 cells and replaced with [ ³ H] -8H-142801 upon binding to the cloned human L3 receptor expressed in CHO cells.

Values characterizing receptor binding (ρ ^ ₅₀ ), in the case 1ι-ΝΚ | vary from 10 to 6 among the compounds of this invention.

Example Ό2. Signal Transmission (8T)

This test allows us to evaluate the functional antagonistic activity against ΝΚ ₁ ίη Y1! Go. In order to measure the concentration of intracellular Ca ⁺⁺ , the cells were grown on 96-well (black walls / clear bottom) Sok! Ag plates for 2 days until fusion was achieved. Then the cells are incubated with 2 μm P1io3 in содержащей containing 0.1% BSA and 2.5 mM probenecid, for 1 h at 37 ° C. After incubation, the cells are washed with 3x Krebs buffer (140 mM No. C1, 1 mM MdCl ₂ x 6H ₂ O, 5 mM KCl, 10 mM glucose, 5 mM HEPE8; 1.25 mM CaCl ₂ ; pH 7.4) containing 2.5 mM probenecid and 0.1% BSA (Ca ⁺⁺ buffer). Cells are incubated with different concentrations of antagonists for 20 minutes at room temperature and then the Ca ⁺⁺ signals are measured using a Nioghepsse Riade plate reader (PIRC from Mo1eci1ag Peukek, CgMeu, Epdap). The peak of Ca ⁺⁺ transfer is taken as the relevant signal, the average values from the corresponding wells are analyzed using the method described below.

Sigmoidal dose-response curves are analyzed by computer-aided curve selection using the SgarNRab program. The EC ₅₀ value is the concentration at which the effect of the compound is 50% of the maximum. Upon receipt of the averaged curves, the maximum response to the antagonist is taken as 100%. Antagonistic responses are evaluated by TC ₅₀ values calculated by the nonlinear regression method.

The ρΚΡ ₀ data for some compounds obtained in the analysis of signal transmission are presented in Table. 4. The last column indicates, without limitation, the most suitable application for compounds.

- 22 014239

Table 4. Pharmacological results of signal transmission analysis for some compounds (η.ά. = not determined)

Connection No. ΝΚ] p1C ₅ . ΝΚϊ p! C " ΝΚ ₃ Suitable FOR 2-5 7.4 3.6 5.7 ΝΚι 2-6 7.3 5.3 5.5 ΝΚι 1-5 7.3 5.2 <5 ΝΚ! 1-9 7.3 5.2 <5 ΝΚ, 1-6 7.2 5.8 <5 ΝΚ! 2-3 7.2 5.5 5.2 ΝΚ, 1-7 7.0 5.5 <5 ΝΚ] 2-4 7.0 5.6 5.0 ΝΚ! 2-8 7.0 5.2 5.4 ΝΚ, 1-8 7.0 5.2 <5 ΝΚ! 2-9 6.9 5.3 5.4 ΝΚ! 2-7 6.8 5.2 5.6 ΝΚ, 1-11 6.8 5.0 <5 ΝΚι 1-12 6.7 5.4 <5 ΝΚι 1-10 6.7 5.3 <5 ΝΚ, 1-4 6.7 5.2 <5 ΝΚι 1-3 6.6 5.4 <5 ΝΚι 2-10 6.6 5.3 <5 ΝΚ, 1-2 6.2 <5 <5 ΝΚ)

E. Examples of compositions

The term active ingredient (Α.Ι.) in these examples refers to a compound of formula (Ι), its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms, Ν-oxides and their prodrugs.

Example E1. Drops for oral administration

500 g Α.Ι. dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of polyethylene glycol at 6080 ° C. After cooling to 30-40 ° C, 35 L of polyethylene glycol is added and the mixture is thoroughly mixed. Then add a solution of 1750 g of saccharin sodium in 2.5 l of purified water, add 2.5 l of cocoa flavoring and polyethylene glycol s. | .K with stirring. up to 50 l, receiving an oral solution containing 10 mg / ml Α.Ι. The resulting solution is poured into suitable containers.

Example E2. The oral solution, g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate is dissolved in 4 l of boiling purified water. First, 10 g of 2,3-dihydroxybutanedicarboxylic acid and then 20 g of данного.Ι are dissolved in 3 l of this solution. The last solution is combined with the remaining part of the first solution and 12 L of 1,2,3-propanediol and 3 L of a 70% sorbitol solution are added. 40 grams of sodium saccharin are dissolved in 0.5 l of water and 2 ml of raspberry extract and 2 ml of gooseberry extract are added. The last solution is combined with the first, water is added. up to 20 l, receiving an oral solution containing 5 mg of the active ingredient per teaspoon (5 ml). The resulting solution is poured into suitable containers.

Example E3. Film coated tablets

Getting the pill base

A mixture of 100 g Α.Ι., 570 g of lactose and 200 g of starch is thoroughly mixed, moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone in approximately 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then add 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil. All together are thoroughly mixed and pressed into tablets, obtaining 10,000 tablets, each of which contains 10 mg of the active ingredient.

- 23 014239

Coating

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol, a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane is added. Then add 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the first and then 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of a concentrated dye suspension are added, after which the resulting mixture is homogenized. The bulk of the tablets are coated with the resulting mixture in a coating apparatus.

Example E4. Injection

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate are dissolved in approximately 0.5 l of boiling water for injection. After cooling to about 50 ° C., 4 g of lactic acid, 0.05 g of propylene glycol and 4 g of Α.Ι. are added with stirring. The solution was cooled to room temperature and water was added for injection d. 8. up to 1 l, obtaining a solution containing 4 mg / ml Α.Ι. The solution is sterilized by filtration and poured into sterile containers.

Claims (15)

CLAIM 1. The compound of General formula (I) K ¹ O. / \ - (CH ₂ ) _t / ^CH ASNAAT) ₍ / - ^{Ζ— Ν} X Ν — A1k-y — A1k — 1_ E ² —X Asn ₂ ) _p \ sn ₂ 4 (SnX its pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms and Ν-oxides, where K ² is Ag ² ; X is a covalent bond; O is O; K ^{1 is} selected from the group consisting of Ar ¹ -alkyl and di (Ag ¹ ) alkyl; η and m are both equal to 1; Ζ stands for covalent bond; y to, p, s. | denote integers independently of one another equal to zero, 1, 2 or 3; provided that the sums (ί + k) and (p + c |) are 3; T denotes = O in the alpha position with respect to the atom Ν, and ΐ denotes an integer equal to 0 or 1; each A1k independently represents a covalent bond; a bivalent saturated hydrocarbon radical containing 1 carbon atom; Υ represents a covalent bond or a bivalent radical of the formula —C (═O) -; B is selected from the group consisting of hydrogen, alkyl, Ar ^{3 4} or He! ² ; Ar ¹ is phenyl; Ar ² is phenyl optionally substituted with 1 or 2 trifluoromethyl groups; Ar ³ is phenyl; Not! ² represents a monocyclic heterocyclic radical selected from the group consisting of tetrahydrofuranyl, furanyl, thiadiazolyl, pyrazinyl and thienyl, where each monocyclic heterocyclic radical may optionally be substituted at any atom with one or more radicals selected from alkyl; alkyl means a linear or branched saturated hydrocarbon radical containing from 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon radical containing from 3 to 6 carbon atoms. 2. The compound according to claim 1, characterized in that the spiro fragment has the formula (£ 6) or (£ 8), in which all variables have the same definition as in formula (I), and denotes a piperidinyl fragment of formula (I), and b denotes a fragment A1k ^ -A1k-b of formula (I). 3. The compound according to any one of claims 1, 2, characterized in that K ¹ denotes benzyl attached to the 2 position. 4. The compound according to any one of claims 1 to 3, characterized in that the fragment K ² —X — C (= O) - means 3,5-24 24 014239 di- (trifluoromethyl) phenylcarbonyl. 5. The compound according to any one of claims 1 to 4, characterized in that b is selected from the group consisting of hydrogen, tert-butyl, isopropyl, tetrahydrofuranyl, furanyl, thienyl, thiadiazolyl, phenyl and pyrazinyl. 6. The compound according to any one of claims 1 to 5, where I ¹ is benzyl; _), k, p, s. | denote integers independently equal to zero, 1, 2 or 3; provided that the sums (| + k) and (p + b) are 3; ΐ denotes an integer equal to 0; Υ represents a covalent bond or a bivalent radical of the formula —C (═O) -; B is selected from the group consisting of hydrogen, alkyl, Ar ³ and He! ² ; Ar ³ is phenyl. 7. The compound according to claim 1, selected from the group of compounds 8. The use of a compound according to any one of claims 1 to 7 as a medicine. 9. The use of a compound according to any one of claims 1 to 7 as a drug that is active when administered orally and is able to penetrate the central nervous system. 10. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of tachycinin-mediated conditions. 11. The use of a compound according to claims 1-7 for the manufacture of a medicament for the treatment and / or prevention of schizophrenia, vomiting, anxiety and depression, irritable bowel syndrome (ΙΒ8), circadian rhythm disturbances, preeclampsia, nociception, visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (SORE), and urination disorders such as urinary incontinence. 12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 7. 13. The method of obtaining the pharmaceutical composition according to p. 12, characterized in that the pharmaceutically acceptable carrier is uniformly mixed with a therapeutically effective amount of a compound according to any one of claims 1 to 7. 14. A method of obtaining a compound of formula (1a), comprising reductive Ν-alkylation of an intermediate of formula (ΙΙ) with an intermediate of formula (ΙΙΙ) to obtain the final compound of formula (1a), where all variables have the definition specified in claim 1, inert - a solvent and (P) (III) (1a), if necessary, converting a compound of formula (1a) into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treating a base m, or, conversely, the conversion of an acid addition salt to a free base by treatment with alkali, the conversion of a base addition salt 25 014239 salts into the free acid by treatment with an acid; and, if necessary, obtaining stereochemical isomeric forms, Ν-oxides and tertiary ammonium salts of these compounds. 15. The method according to 14, characterized in that the fragment A1k-Y-A1k-b in the compounds of formulas (III) and Yes) is benzyl. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2